Urinary bladder cancer encompasses a spectrum of neoplasms ranging from low-grade papillary tumors to high-grade aggressive tumors. The majority of tumors are of the former type and characteristically recur following surgical resection. Our overall objective is to investigate both mechanisms of urinary bladder carcinogenesis and methods for prevention of recurrence of neoplasms. The immediate objective is to obtain evidence supporting our working hypothesis which states that "the progression to cancer of initiated bladder epithelial cells is aided by factors which stimulate cell replication." The factors include the specific urinary components capable of inducing ornithine decarboxylase (ODC), and chemical and physical trauma stimulating continued or repeated regenerative hyperplasia. The specific aims to test the hypothesis are: 1) to clarify the mechanism(s) of the inhibitory actions demonstrated by an irreversible inhibitor of ODC, Alpha-difluoromethylornithine, on carcinogenesis in the heterotopically transplanted urinary bladder system, 2) to determine whether the carcinogenesis in the natural bladder system can be similarly inhibited by chronic oral administration of DFMO, and 3) to determine whether the diffuse papillomatosis of the rat urinary bladder which develops in association with bladder calculi without known prior carcinogen exposure, is reversible following removal of the physical stimulus (calculus). These studies will be conducted using the heterotopically transplanted urinary bladder system developed in our laboratory, and natural bladders.